In the pharmaceutical industry, the controlled heating of sample media in vessels is an important step in sample preparation procedures. Examples of such procedures include those performed for the purpose of testing and analyzing the rate at which dosages release from pharmaceutical products such as tablets, filled capsules or transdermal patches. The dosages are released in solutions under controlled conditions which may or may not be representative of the human digestive process, contact with the skin, or implantation within the body. The procedural steps, test duration, dissolution medium, and apparatus employed in any given dissolution test must comply with United States Pharmacopeia (USP) guidelines in order for the test to be accepted as valid for the specific dosage or delivery system tested.
For instance, the general requirements of Section 711 (Dissolution) of USP 23-NF18, Ninth Supplement, Nov. 15, 1998, specify a particular apparatus, termed "Apparatus 1," which includes a covered vessel made of plastic, glass or other inert, transparent material that does not absorb, react, or interfere with the specimen being tested; a motor; a metallic drive shaft; and a cylindrical basket. Other devices may be specified from time to time for stirring, mixing or retaining the delivery system during the test procedure.
The vessel may be cylindrical with a hemispherical or flat bottom and sides which are flanged at the top. The dimensions of the vessel are specified according to the nominal volumetric capacity of the vessel. A fitted cover can be used to retard evaporation from the vessel and, when used, must provide sufficient openings to allow the ready insertion of a thermometer and withdrawal of specimens. Also included are requirements for the dimensions, construction material, position in relation to the vessel, and performance of the shaft and other operative components. Importantly, the vessel must be either partially immersed in a water bath of placed in a heating jacket to hold the temperature inside the vessel at 37.+-.0.5.degree. C. or other specified temperature. When using a water bath, the bath fluid must be kept in constant, smooth motion.
FIG. 1 illustrates a conventional dissolution testing apparatus generally designated 10. Apparatus 10 includes a main housing or head 12 containing a programmable systems control module. Head 12 is situated above a vessel plate 14 and a water bath container 16, and is typically motor-driven for vertical movement toward and away from vessel plate 14. Peripheral elements located on head 12 include an LCD display 18 for providing menus, status and other information; a keypad 21 for providing user-inputted operation and control of spindle speed, temperature, test start time, test duration and the like; and readouts 23 for displaying information such as RPM, temperature, elapsed run time, or the like. Water must be heated and circulated through water bath container 16 by means such as external heater and pump modules (not shown), which may be combined into a single heater/circulator module. Water bath container 16 thus requires a fluid transfer means such as tubing 25, as well as a drain line 27 and valve 29.
Vessel plate 14 supports a plurality of vessels 31 extending into the interior of water bath container 16. Typically, three, four, six or eight vessels 31 can be supported. Each vessel 31 has a standard shape characterized by a lateral cylindrical section 31A, a bottom hemispherical (or flat) section 31 B, and a flanged section 31C around the mouth of vessel 31. Vessels 31 are locked and centered in place on vessel plate 14 by means such as ring lock devices or clamps (not shown). A stirring element including a motor-driven spindle 37A and paddle 37B operates in each vessel 31. Individual clutches 39 can be provided to alternately engage and disengage power to each spindle 37A. A dosage delivery module 41 is used to preload and drop dosage units (e.g., tablets) into each vessel 31 at prescribed times and bath (or vessel) temperatures. An automated sampling manifold 45 lowers and raises sampling cannulae 47 into and out of each respective vessel 31. Sampling manifold 45 can also be vertically movable between head 12 and vessel plate 14. Sampling cannulae 47 operate in conjunction with a bidirectional peristaltic pump (not shown), and are used during the dissolution testing procedure to periodically withdraw samples from the vessel media for analysis. Samples could also be taken manually using pipettes and/or sampling cannula/syringe assemblies. Miniature temperature probes 49 associated with each vessel 31 can also be located on sampling manifold 45.
In a typical operation, dosage units are dropped into the bottoms of each solution-containing vessel 31 and each paddle 37B rotates at a predetermined rate and duration within the test solution as the dosage units dissolve. In other types of tests, a cylindrical basket (not shown) loaded with a dosage unit is substituted for each paddle 37B and rotates within the test solution. For any given vessel 31, the temperature of the test solution must be maintained at a prescribed temperature (e.g., 37.degree. C.). Solution temperature is maintained by immersion of vessel 31 in the water bath of water bath container 16. Accordingly, the temperature of the test solution is dependent upon, and thus indirectly controlled by, the temperature of the water bath which in turn is dictated by the external heating means employed. Temperature probe 49 is used to monitor the test solution temperature, and can be any suitable type of transducer such as a thermistor.
As recognized by those skilled in the art, the use of a water bath in connection with an apparatus such as dissolution testing apparatus 10 has some drawbacks. First, water bath container 16 is necessarily large in order to accommodate the immersion of several vessels 31, and hence requires a significant volume of water to serve as the medium for transferring heat energy to the media or solution contained in vessels 31. Consequently, an undue amount of time and energy is required to initially dispense the volume of heated water into water bath container 16 and bring each vessel 31 to the desired set point temperature. The volume of water also adds to the overall weight of apparatus 10. Second, an external heater and water circulation system is required. It might be possible to eliminate the water circulation system by providing an external resistive heating plate or coil to heat the water bath. Such a resistive heating element, however, would necessarily be quite large in order to heat the entire volume of the water bath, require a large amount of electrical energy to operate, and would not appreciably reduce the amount of startup time required to bring vessels 31 to a desired set point temperature. Third, the water bath system does not allow for individualized control of each vessel 31. The ability to control the heating profile of a given vessel 31 or group of vessels 31 independently and distinct from other vessels 31 of dissolution testing apparatus 10 would be quite useful during many types of procedures. Fourth, biological growth, scaling, and other impurities tend to collect in the water bath, such that the use of the water bath entails cleaning maintenance and the addition of preservatives or additives, all of which adds to the cost of the water bath system.
One approach to eliminating the need for a water bath and controlling the temperatures of individual vessels, while still conforming to USP dissolution requirements, is disclosed in U.S. Pat. No. 5,589,649 to Brinker et al. The embodiments disclosed therein provide individual flexible, resistive heater elements attached to and wrapped around the lateral cylindrical section of the outside wall of each vessel. Each heater element is divided into horizontally oriented heating areas having differing power ratings (e.g., 100 W, 200 W, etc.). The heating areas are controlled by the associated dissolution testing apparatus through lead wires. Each heater element is required to be held in place on its vessel by a spring-loaded stainless steel jacket. The jacket is profiled to provide a gap between the jacket and the heater element. Because the vessel is not immersed in a heat-providing water bath, a reflective coating is attached to the hemispherical section of the vessel in order to reduce heat loss from the vessel and reduce the time required to bring the test solution to the desired solution temperature.
The temperature control system disclosed in Brinker et al. requires the use of a modified stirring element for each vessel. The shaft of the modified stirring element is hollow. A temperature sensor such as a resistive thermal device (RTD), thermocouple or thermistor is located near the bottom of the hollow interior of the stirring element shaft in physical thermal contact therewith, and generates signals representative of temperature measured within the vessel. Power to this temperature sensor and the signals generated thereby are transmitted through a cable running through the hollow length of the stirring element shaft, through a signal transfer device located at the top of the shaft, and through a second cable connected to the control circuitry of the dissolution testing apparatus.
The requisite jacket is disadvantageous in that it impairs or, in some cases, almost completely obstructs a view of the contents of the vessel and the stirring element operating therein. This problem is especially critical in view of the fact that USP Section 711 expressly indicates that the dissolution apparatus should preferably permit observation of the specimens and stirring element during testing. Moreover, the jacket does not completely insulate the vessel from external thermal influences such as room air conditioning, heating, ventilation, and open doors. In addition, the customized stirring element and its requisite electrical components, as well as the need for the addition of a reflective coating, are believed to be unduly complex and expensive solutions to the problems presented by current vessel heating systems.
Accordingly, there remains a need for a more practical, effective, and energy efficient solution to providing a vessel heating system that does not require a water bath and that can independently control individual vessels in a vessel-containing system such as a dissolution testing apparatus. The present invention is provided to address these and other problems associated with vessel heating systems.